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Nervous Healers' Agonizing Touch

Most pain is a wake-up call to danger, intended to make sure your hand doesn't linger on a hot stove, for instance. But pain without any purpose is just pain, and some people suffer it for no obvious reason. New results reveal that the source of such chronic pain could lie in a previously overlooked type of cell and might one day lead to successful treatment of a long-lasting scourge.

Sometimes pain caused by an injury, such as a pinched nerve, persists even after the injury has healed. This mysterious, often debilitating, pain has stumped doctors and scientists. Most have focused on communication between nerve cells. Some evidence has suggested that another kind of cell might be involved. These so-called microglia function as the immune cells of the nervous system, repairing damaged nerves and removing dead tissue.

The new study implicates microglia and identifies a particular receptor on the cells that appears to play a critical role in chronic pain. Neurochemist Kazuhide Inoue of the National Institute of Health Sciences in Tokyo and his colleagues simulated pathological pain in rats by cutting a sensory nerve, which caused the wounded animal to flinch at even a light touch. The researchers then injected a compound into the rats' spinal cords that interfered with molecules called P2X receptors, which sit in the cell membrane and control the flow of ions into the cell. Of the seven types of P2X receptor, two occur in pain-sensing neurons. Specifically blocking these two receptors did not alleviate the rats' sensitivity to touch. Blocking all seven, however, eased the pain. Another receptor, called P2X4, is only found on microglia, and when the researchers found that microglia congregated at the spinal cord, specifically on the side where the damaged nerve joined the cord, they suspected that P2X4 might be involved. To test this, they injected the cells directly into the spinal cords of healthy rats. These rats soon flinched just as much as the injured rats.

"For much of the pain world, this is a powerful statement that you can no longer ignore glia," says pain researcher Edwin McCleskey of the Oregon Health and Science University in Portland. The results raise the question, McCleskey adds, of how microglia detect nerve damage. Answers to that and other questions could help lead to therapies for devastating chronic pain.